Role of Mitochondrial Dysfunction in the Pathogenesis of Cisplatin-Induced Myotube Atrophy
Role of Mitochondrial Dysfunction in the Pathogenesis of Cisplatin-Induced Myotube Atrophy
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DOI：
10.1248/bpb.b22-00171
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发表时间：
2022-06-01
影响因子：
2
通讯作者：
Takeda, Hiroshi
中科院分区：
文献类型：
--
作者：
Matsumoto, Chinami;Sekine, Hitomi;Takeda, Hiroshi
在顺铂化疗期间通常观察到肌肉萎缩，导致癌症患者的QOL降低。顺铂治疗引起的骨骼肌质量减少是由于泛素连接酶Atrogin-1和MuRF 1的激活，但确切的机制尚不清楚。在这项研究中，我们调查了线粒体功能障碍，包括活性氧（ROS）的产生和ATP的生产，在顺铂诱导的肌肉萎缩的可能参与。用顺铂处理Skeleton C2 C12肌管，并评估基因和蛋白质表达。线粒体质量，膜电位，和ROS水平测定使用荧光染料。线粒体呼吸功能，ATP生产率和糖酵解能力也进行了分析，使用细胞外流量分析仪。采用气相色谱-串联质谱法进行代谢组学分析。顺铂治疗通过激活泛素-蛋白酶体系统降低肌球蛋白重链表达。顺铂治疗后观察到ROS产生增加，随后出现凋亡相关基因表达的显著变化，线粒体质量、膜电位、呼吸和ATP产生减少。糖酵解能力和三羧酸（TCA）循环代谢产物水平与顺铂治疗降低。线粒体靶向的抗氧化剂线粒体醌甲磺酸盐阻止Atrogin-1基因表达的上调，并恢复肌球蛋白重链水平，伴随着ROS生成的减少，但不是线粒体ATP的产生。我们的结论是顺铂诱导的肌管萎缩与线粒体功能障碍有关。减少ROS的产生，而不是促进ATP的产生，可能是预防顺铂诱导的肌肉萎缩的有用的治疗策略。
Muscle atrophy is commonly observed during cisplatin chemotherapy, leading to a reduced QOL in cancer patients. Reduced skeletal muscle mass caused by cisplatin treatment results from the activation of ubiquitin ligases-Atrogin-1 and MuRF1, but the precise mechanisms are poorly understood. In this study, we investigated the possible involvement of mitochondrial dysfunction, including reactive oxygen species (ROS) generation and ATP production, in cisplatin-induced muscle atrophy. Skeletal C2C12 myotubes were treated with cisplatin, and gene and protein expression were evaluated. Mitochondrial mass, membrane potential, and ROS levels were measured using fluorescent dyes. Mitochondrial respiratory function, ATP production rates, and glycolytic capacity were also analyzed using an extracellular flux analyzer. Metabolomic analyses were performed using gas chromatography-tandem mass spectrometry. Cisplatin treatment reduced myosin heavy chain expression by activating the ubiquitin-proteasome system. Increased ROS production was observed after cisplatin treatment, followed by significant changes in apoptosis-related gene expression and decrease in mitochondrial mass, membrane potential, respiration, and ATP production. Glycolytic capacity and tricarboxylic acid (TCA) cycle metabolite levels were reduced with cisplatin treatment. Mitochondria-targeted antioxidant mitoquinone mesylate prevented up-regulation of Atrogin-1 gene expression and restored myosin heavy chain levels, accompanied by a decrease in ROS generation, but not mitochondrial ATP production. We concluded that cisplatin-induced myotube atrophy was associated with mitochondrial dysfunction. Reducing ROS generation, rather than promoting ATP production, could he a useful therapeutic strategy for preventing cisplatin-induced muscle atrophy.